Substituted arylalkylamines as neurokinin antagonists

- Schering Corporation

Compounds represented by the structural formula ##STR1## or a pharmaceutically acceptable salt thereof are disclosed, wherein: A.sup.1 is --CH.sub.2 R.sup.6, --OR.sup.6, --N(R.sup.6)(R.sup.7), --S(O).sub.e R.sup.13, --(C(R.sup.6)(R.sup.7)).sub.1-6 --OR.sup.6, --(C(R.sup.6)(R.sup.7).sub.1-6 --N(R.sup.6)(R.sup.7) or --(C(R.sup.6) (R.sup.7)).sub.1-6 --S(O).sub.e R.sup.13 and A.sup.2 is H, or A.sup.1 and A.sup.2 together are .dbd.O, .dbd.C(R.sup.6)(R.sup.7), .dbd.NOR.sup.6 or .dbd.S;Q is phenyl, naphthyl, --SR.sup.6, --N(R.sup.6)(R.sup.7), --OR.sup.6 or heteroaryl;T is H, aryl, heterocycloalkyl, heteroaryl, cycloalkyl or bridged cycloalkyl;b is 0, 1 or 2;b.sub.1 is 1 or 2;X is a bond, --C(O)--, --O--, --NR.sup.6 --, --S(O).sub.e --, --N(R.sup.6)C(O)--, --C(O)N(R.sup.6)--, --OC(O)NR.sup.6 --, --OC(.dbd.S)NR.sup.6 --, --N(R.sup.6)C(.dbd.S)O--, --C(.dbd.NOR.sup.6)--, --S(O).sub.2 N(R.sup.6)--, --N(R.sup.6)S(O).sub.2 --, --N(R.sup.6)C(O)O-- or --OC(O)--;R.sup.6, R.sup.7, R.sup.8a, and R.sup.13 are H, alkyl, hydroxyalkyl, alkoxy alkyl, phenyl or benzyl; or R.sup.6 and R.sup.7, together with the nitrogen to which they are attached, form a ring;R.sup.9 and R.sup.9a independently are R.sup.6 or --OR.sup.6 ;Z is optionally substituted ##STR2## wherein g is 0-3 and h is 1-4, provided the sum of h and g is 1-7; wherein the aryl, phenyl, benzyl, naphthyl, heterocycloalkyl and heteroaryl groups are optionally substituted. Methods of treating asthma, cough, bronchospasm, imflammatory diseases, and gastrointestinal disorders with said compounds, and pharmaceutical compositions comprising said compounds are disclosed.

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Claims

1. A compound represented by the structural formula ##STR51## or a pharmaceutically acceptable salt thereof, wherein: A.sup.1 is --CH.sub.2 R.sup.6, --OR.sup.6, --N(R.sup.6)(R.sup.7), --S(O).sub.e R.sup.13, --(C(R.sup.6)(R.sup.7)).sub.1-6 --OR.sup.6, --(C(R.sup.6)(R.sup.7).sub.1-6 --N(R.sup.6)(R.sup.7) or --(C(R.sup.6) (R.sup.7)).sub.1-6 --S(O).sub.e R.sup.13 and A.sup.2 is H, or A.sup.1 and A.sup.2 together are.dbd.O,.dbd.C(R.sup.6)(R.sup.7),.dbd.NOR.sup.6 or.dbd.S;

Q is R.sup.5 -phenyl, R.sup.5 -naphthyl, --SR.sup.6, --N(R.sup.6)(R.sup.7), --OR.sup.6 or R.sup.5 -heteroaryl;
T is H, R.sup.4 -aryl, R.sup.4 -heterocycloalkyl, R.sup.4 -heteroaryl, R.sup.4 -cycloalkyl or R.sup.10 -bridged cycloalkyl;
b is 0, 1 or 2;
b.sub.1 is 1 or 2;
X is a bond, --C(O)--, --O--, --NR.sup.6 --, --S(O).sub.e --, --N(R.sup.6)C(O)--, --C(O)N(R.sup.6)--, --OC(O)NR.sup.6 --, --OC(.dbd.S)NR.sup.6 --, --N(R.sup.6)C(.dbd.S)O--, --C(.dbd.NOR.sup.6)--, --S(O).sub.2 N(R.sup.6)--, --N(R.sup.6)S(O).sub.2 --, --N(R.sup.6)C(O)O-- or --OC(O)--;
R.sup.4 and R.sup.5 are independently 1-3 substituents independently selected from the group consisting of H, halogeno, --OR.sup.6, --OC(O)R.sup.6, --OC(O)N(R.sup.6)(R.sup.7), --N(R.sup.6)(R.sup.7), C.sub.1-6 alkyl, --CF.sub.3, --C.sub.2 F.sub.5, --COR.sup.6, --CO.sub.2 R.sup.6, --CON(R.sup.6)(R.sup.7), --S(O).sub.e R.sup.13, --CN, --OCF.sub.3, --NR.sup.6 CO.sub.2 R.sup.16, --NR.sup.6 COR.sup.7, --NR.sup.8 CON(R.sup.6)(R.sup.7), R.sup.15 -phenyl, R.sup.15 -benzyl, NO.sub.2, --N(R.sup.6)S(O).sub.2 R.sup.13 or --S(O).sub.2 N(R.sup.6)(R.sup.7); or adjacent R.sup.4 substituents or adjacent R.sup.5 substituents can form a --O--CH.sub.2 --O-- group; and R.sup.4 can also be R.sup.15 -heteroaryl;
R.sup.6, R.sup.7, R.sup.8, R.sup.8a, and R.sup.13 are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2 -C.sub.6 hydroxyalkyl, C.sub.1 -C.sub.6 alkoxy-C.sub.1 -C.sub.6 alkyl, R.sup.15 -phenyl, and R.sup.15 -benzyl; with the proviso that when A.sup.1 is CH.sub.2 R.sup.6, R.sup.6 is not hydrogen, or R.sup.6 and R.sup.7, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of --O--, --S-- and --N(R.sup.19)--;
R.sup.9 and R.sup.9a are independently selected from the group consisting of R.sup.6 and --OR.sup.6, provided that when R.sup.9 is OH, X is a bond, --C(O)--, --N(R.sup.6)C(O)-- or --C(.dbd.NOR.sup.6)--;
R.sup.10 is independently selected from the group consisting of H and C.sub.1-6 alkyl;
R.sup.15 is 1 to 3 substituents independently selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halogeno, --CF.sub.3, --C.sub.2 F.sub.5, --COR.sup.10, --CO.sub.2 R.sup.10, --C(O)N(R.sup.10).sub.2, --S(O).sub.e R.sup.10, --CN, --N(R.sup.10)COR.sup.10, --N(R.sup.10)CON(R.sup.10).sub.2 and --NO.sub.2;
R.sup.16 is C.sub.1-6 alkyl, R.sup.15 -phenyl or R.sup.15 -benzyl;
R.sup.19 is H, C.sub.1 -C.sub.6 alkyl, --C(O)N(R.sup.10).sub.2, --CO.sub.2 R.sup.10, --(C(R.sup.8)(R.sup.9)).sub.f --CO.sub.2 R.sup.10 or --(C(R.sup.8)(R.sup.9)).sub.u --C(O)N(R.sup.10).sub.2;
f is 1-6;
u is 0-6;
Z is ##STR52## and R.sup.28 is OH, C.sub.1 -C.sub.6 alkoxy or --C(O)NH.sub.2.

2. A compound of claim 1 wherein X is --O--, --NR.sup.6 --, --N(R.sup.6)C(O)--, --OC(O)NR.sup.6 -- or --N(R.sup.6)C(O)O--.

3. A compound of claim 1 wherein T is R.sup.4 -aryl or R.sup.4 -heteroaryl.

4. A compound of claim 1 wherein Q is R.sup.5 phenyl, R.sup.5 -naphthyl or R.sup.5 -heteroaryl.

5. A compound of claim 1 wherein A.sup.1 is --OR.sup.6, --N(R.sup.6)(R.sup.7), --S(O).sub.e R.sup.13 or --(C(R.sup.6)(R.sup.7)).sub.1-6 --N(R.sup.6)(R.sup.7) and A.sup.2 is H; or A.sup.1 and A.sup.2 together are.dbd.O,.dbd.C(R.sup.6)(R.sup.7) or.dbd.NOR.sup.6.

6. A compound of claim 1 wherein b is 0 or 1, b.sub.1 is 1, X is --NR.sup.6 -- or --N(R.sup.6)C(O)--, and R.sup.8a and R.sup.9a are independently selected from the group consisting of hydrogen, hydroxyalkyl and alkoxyalkyl.

7. A compound of claim 6 wherein T is phenyl substituted by two substituents selected from the group consisting of C.sub.1 -C.sub.6 alkyl, halogeno, --CF.sub.3 and C.sub.1 -C.sub.6 alkoxy.

8. A compound of claim 7 wherein Q is phenyl di-substituted by halogeno, naphthyl or benzothienyl.

9. A compound of claim 8 wherein A.sup.1 is --OR.sup.6, --N(R.sup.6)(R.sup.7), --S(O).sub.e R.sup.13 or --(C(R.sup.6)(R.sup.7)).sub.1-6 --N(R.sup.6)(R.sup.7) and A.sup.2 is H; or A.sup.1 and A.sup.2 together are.dbd.O,.dbd.C(R.sup.6)(R.sup.7) or.dbd.NOR.sup.6.

10. A method of treating asthma, cough or bronchospasm comprising administering an effective amount of a compound of claim 1 to a mammal in need of such treatment.

11. A pharmaceutical composition comprising an neurokinin inhibitory effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

Referenced Cited
U.S. Patent Documents
5236921 August 17, 1993 Emonds-alt et al.
5350852 September 27, 1994 Emonds-Alt et al.
5534525 July 9, 1996 Miller
Foreign Patent Documents
14909/95 September 1995 AUX
630887 December 1994 EPX
0 680 962 November 1995 EPX
0 699 674 March 1996 EPX
714891 May 1996 EPX
2717802 September 1995 FRX
2274777 August 1994 GBX
93/01169 January 1993 WOX
93/01160 January 1993 WOX
93/23380 November 1993 WOX
94/10146 May 1994 WOX
94/20500 September 1994 WOX
94/29309 December 1994 WOX
95/05377 February 1995 WOX
95/12577 May 1995 WOX
Other references
  • Maggi et al, Eur. J. Pharmacol., 166, (1989), pp. 435-440. Ellis et al, J. Pharmacol. Exp. Ther., 267, 1 (1993), pp. 95-101. Furchgott, Pharm. Rev., 7 (1955), pp. 183-265. Arunlakshana et al, Brit. J. Pharmacol., 14, 48 (1959), pp. 48-58. Danko et al, Pharmacol. Comm., 1, 3 (1992), pp. 203-209. Chung et al, Molecular Pharmacol., 48 (1995), pp. 711-716. Abstract of FR 2,717,802.
Patent History
Patent number: 5789422
Type: Grant
Filed: Oct 28, 1996
Date of Patent: Aug 4, 1998
Assignee: Schering Corporation (Kenilworth, NJ)
Inventors: Gregory A. Reichard (Parsippany, NJ), Robert G. Aslanian (Rockaway, NJ)
Primary Examiner: Ceila Chang
Attorney: Anita W. Magatti
Application Number: 8/742,606
Classifications
Current U.S. Class: Chalcogen Bonded Directly To Ring Carbon Of The Piperidine Ring (514/327); 514/252; 514/255; The Additional Ring Is A Six-membered Hetero Ring Consisting Of One Nitrogen And Five Carbon Atoms (514/318); The Additional Ring Is One Of The Cyclos In A Polycyclo Ring System (514/319); Ring Nitrogen In The Polycyclo Ring System (514/323); Ring Sulfur In The Polycyclo Ring System (514/324); Nitrogen Attached Directly To The Piperidine Ring By Nonionic Bonding (514/329); C=x Bonded Directly To The Piperidine Ring (x Is Chalcogen) (514/330); Nitrogen Attached Indirectly To The Piperidine Ring By Nonionic Bonding (514/331); 1,4-diazines (544/336); Additional Hetero Ring Which Is Unsaturated (544/405); Chalcogen Bonded Directly To Diazine Ring Carbon (544/408); Halogen Attached Directly To The Diazine Ring By Nonionic Bonding (544/409); Chalcogen Attached Directly To A Ring Carbon Of A Piperidine Ring By Nonionic Bonding (546/188); Pyridine Ring Or Partially Hydrogenated Pyridine Ring (546/193); Carbocyclic Ring Containing (546/194); Bicyclo Ring System Which Is Indole (including Hydrogenated) (546/201); The Additional Ring Is A Hetero Ring (546/207); Ring Nitrogen In The Additional Hetero Ring (546/208); Ring Sulfur Or Ring Oxygen In The Additional Hetero Ring (546/209); The Additional Hetero Ring Consists Of One Oxygen And Four Carbons (546/214); Chalcogen And A Carbocyclic Ring Bonded Directly At 4-position (546/217); Having -c(=x)-, Wherein X Is Chalogen, Attached Directly Or Indirectly To The Piperidine Ring By Nonionic Bonding (546/221); Having -c(=x)-, Wherein X Is Chalcogen, Bonded Directly To The Piperidine Ring (546/225); Carbocyclic Ring Bonded Directly At 4-position (546/228); Nitrogen Attached Indirectly To The Piperidine Ring By Nonionic Bonding (546/229); Plural Acyclic Nitrogens Bonded Directly To The Same Carbon Or Single Bonded Directly To Each Other (546/231); Acyclic Nitrogen Single Bonded Directly To Acyclic Nitrogen (546/324); Sulfur And Acyclic Nitrogen Bonded Directly To The Same Carbon (546/331)
International Classification: A61K 31445; C07D21122;